共查询到20条相似文献,搜索用时 109 毫秒
1.
The neuroimmunomodulatory effects of opiates during microbial infections are now well known; however, not much is known during leishmaniasis. Here, we report the effects of morphine on purified approximately 12-kDa component of Leishmania donovani amastigote antigen (LDAA-12)-induced colony-stimulating factor (CSF) production by mouse peritoneal macrophages (PMs) in vitro. Low concentrations (1 x 10(-9) and 1 x 10(-11) M) of morphine significantly (P < 0.05) augmented the production of CSFs, whereas high concentrations (1 x 10(-3) and 1 x 10(-5) M) inhibited CSF production. Morphine exerted a similar concentration-dependent biphasic effect on the LDAA-12-induced elaboration of granulocyte (G)-macrophage (M)-CSF (GM-CSF) and M-CSF by PMs in their conditioned medium, as quantified by using enzyme-linked immunosorbent assay. Furthermore, selective agonists of mu-(DAGO) and delta-(DPDPE) opioid receptors also, respectively, augmented and inhibited the production of CSFs. Pretreatment of PMs with naloxone (1 x 10(-5) M) significantly (P < 0.05) blocked the augmenting effect of morphine. In contrast, at 1 x 10(-5) M, naloxone lacked any effect on the inhibitory effect of morphine; however, its 100-fold higher concentration partially blocked it. This study, apparently for the first time, demonstrates that morphine, via surface opioid receptors, biphasically modulates the LDAA-12-induced CSF production by PMs, in vitro. These results thus show the implications of opiate abuse on the outcome of therapeutic interventions in areas where both visceral leishmaniasis and drug abuse are rampant. 相似文献
2.
B V Krylov A V Derbenev S A Podzorova M I Liudyno A V Kuz'min N L Izvarina 《Rossi?skii fiziologicheski? zhurnal imeni I.M. Sechenova / Rossi?skaia akademiia nauk》1999,85(2):225-236
Morphine was shown to decrease in a dose-dependent manner the effective charge transfer in tetrodotoxin-resistant (TTXr) sodium channel activation system in short-term cultured dorsal root ganglion cells. Morphine seems to interact with opioid receptors because of total block of the binding by naloxone and naltrexone. Neither activating, nor inhibiting G-protein agents exerted any effect on this process. The morphine signal was blocked by extracellular application of 2 x 10(-4) M ouabain. The findings suggest existence of sodium signalling pathway involving receptors, Na+, K(+)-ATPase and the TTXr sodium channels. 相似文献
3.
A Faletti M A Chaud M A Gimeno A L Gimeno 《Prostaglandins, leukotrienes, and essential fatty acids》1988,34(3):147-151
The effects of morphine on the constancy of spontaneous contractions (isometric developed tension = IDT and contractile frequency = CF), in uterine strips isolated from ovariectomized rats and the influence of naloxone, were explored. The inotropic responses to added prostaglandins (PGs) E2 and F2 alpha and the influences of morphine and of morphine in the presence of naloxone on PG actions, were also determined. Moreover, the synthesis and outputs of PGs E and F from uteri and the effects of morphine alone and of morphine plus naloxone, were studied. Morphine (10(-6) M) significantly depressed uterine constancy of IDT during the first hours following delivery, but its action on CF did not differ from controls. Naloxone, neither at 10(-8) M nor at 10(-6) M, altered the negative inotropic influence of morphine on IDT. Exogenous PGs E2 and F2 alpha, stimulated uterine inotropism in a concentration-dependent fashion. Morphine altered dose-response curves for exogenous PGE2, evoking a parallel surmountable shift to the right, but did not affect the inotropic action of added PGF2 alpha. This antagonistic effect of the opioid was not altered by preincubation with naloxone. Basal synthesis and outputs of PGs E and F in uteri from ovariectomized rats were significantly depressed by morphine (10(-6) M) but not altered by incubating tissues with morphine in presence of naloxone. Results are discussed in terms of a presumptive dual action of morphine on uterine motility, i.e., antagonizing PGE2 receptors and inhibiting the synthesis of some PGs by the uterus. These influences of morphine do not appear to be subserved by the activation of mu opioid receptors.(ABSTRACT TRUNCATED AT 250 WORDS) 相似文献
4.
The effects of opiates in various infections are well known; however, very little is known about tuberculosis infection. Therefore, in the present study, we report for the first time, the effects of morphine during murine tuberculosis. Mice were infected intravenously with Mycobacterium tuberculosis H37Rv, administered morphine (0.1-100 mg/kg subcutaneously on day 0 and day +15) and sacrificed on day +30 for CFU enumeration in lungs and spleen. Morphine exerted maximum suppression of infection at 5 mg/kg, and sometimes completes elimination of infection; naloxone, silica and aminoguanidine blocked the protective effect of morphine. In vitro, morphine lacked direct antimycobacterial activity up to 1x10(-4) M concentration, as assessed by radiometric BACTEC method. In macrophage model of infection, morphine showed maximal killing at 1x10(-7) M concentration, the activity was blocked by naloxone and aminoguanidine. These observations suggest that morphine exerts a dose-dependent effect in murine tuberculosis, the protective effect being naloxone-reversible and may involve macrophage-mediated protective mechanisms. These results may be helpful in developing new opioid-like chemical entities against tuberculosis infection. 相似文献
5.
Abstract: Incubation of intact Xenopus oocytes with the opioid radioligand [3 H]diprenorphine (0.5 n M ) resulted in specific binding of 1.7 ± 0.3 fmol per oocyte. Morphine (10 μ M ) inhibited the uptake of 45 Ca2+ into the oocyte by 66 ± 9%. The opioid antagonist naltrexone partially blocked this effect of morphine. Preincubation of oocytes with morphine (10 μ M , 2 min) partially inhibited the fast and slow responses of the oocyte to acetylcholine by 26 and 52%, respectively. We conclude that native Xenopus oocytes possess opioid receptors that may modulate the muscarinic response by limiting calcium influx into the cell. 相似文献
6.
Messmer D Hatsukari I Hitosugi N Schmidt-Wolf IG Singhal PC 《Molecular medicine (Cambridge, Mass.)》2006,12(11-12):284-290
We evaluated the effect of morphine on human dendritic cells (DCs). Interestingly, immature DCs were found to express all 3 (mu, kappa, delta) opioid receptors on the cell surface. Chronic morphine treatment (10(-8) to 10(-12) M) during the development of DCs from monocytes augmented LPS-induced upregulation of HLA-DR, CD86, CD80, and CD83 and increased the T cell stimulatory capacity of DCs, which could be inhibited by naloxone, an opioid receptor antagonist. The change in surface phenotype was paralleled by a p38 MAPK-dependent decrease in IL-10 and increase in IL-12 secretion. Our data indicate that morphine exerts an immunostimulatory effect by modulating LPS-induced DC maturation. 相似文献
7.
P P Singh S Singh V C Dhawan W Haq K B Mathur G P Dutta R C Srimal B N Dhawan 《Journal of biological regulators and homeostatic agents》1991,5(4):142-146
Methionine-enkephalin (M-Enk) and its analogue compound 82/205 (10(-5) and 10(-6) M) inhibited elaboration of Plasmodium cynomolgi total antigens soluble in culture medium (P.c.SA)-induced colony-stimulating factors (CSFs) by monkey blood monocyte-derived macrophages, in vitro. Paradoxically, lower concentrations (10(-7)-10(-9) M) of both the peptides greatly augmented CSFs elaboration; 82/205 appeared to be nearly 2.3-fold more potent. Naloxone (10(-5) M) pretreatment of macrophages inhibited only the M-Enk- and 82/205-induced enhanced CSFs elaboration, suggesting an opiate receptors-mediated mechanism of action. None of the peptides or naloxone (10(-5)-10(-9) M) had any direct effect on the CSF elaboration by unstimulated macrophages. 相似文献
8.
T Sasaki N F Kassell D M Turner J C Torner H C Coester 《Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine (New York, N.Y.)》1984,177(3):422-427
The pharmacological properties of naloxone on vascular smooth muscle in vitro were examined using canine mesenteric arterial segments. Naloxone exerted two different effects on the artery: (A) naloxone at a high concentration (3 X 10(-4) M) produced a nonspecific vasodilation; and (B) naloxone at lower concentrations (3 X 10(-7), 3 X 10(-6), and 3 X 10(-5) M) augmented the vasoconstrictor effects of epinephrine and norepinephrine without altering KCl- or serotonin-induced constriction. Naloxone's augmenting effect on epinephrine-induced constriction was dose dependent. Even when the arterial strips were incubated in low calcium (0.8 mM) or calcium free Kreb's solution, naloxone (3 X 10(-5) M) still augmented epinephrine-induced constriction. With respect to naloxone's effect on another alpha-adrenoreceptor agonist, naloxone (3 X 10(-5) M) failed to alter phenylephrine-induced constriction. Naloxone's augmenting effect on norepinephrine-induced constriction was abolished when the specimens were incubated with 10(-5) M normetanephrine, while naloxone (3 X 10(-5) M) still augmented the constriction even when the specimens were incubated with 10(-5) M cocaine. These results suggest that naloxone at lower concentrations may augment the constrictor responses to catecholamines, at least in part, by inhibiting the extraneuronal uptake of those catecholamines. 相似文献
9.
De Rensis F Cosgrove JR Willis HJ Hofäcker S Foxcroft GR 《Journal of reproduction and fertility》1999,116(2):243-251
Administration of morphine to ten suckled and nine zero-weaned (piglets removed immediately after farrowing) sows was used to investigate the apparent absence of opioid regulation of LH and prolactin secretion in early lactation. Blood samples were collected at 10 min intervals at 24-30, 48-54, 72-78 h post partum, and for a 12 h period from 08:00 to 20:00 on day 10 after farrowing. Morphine (0.1 mg kg-1) was administered as three i.v. bolus injections at intervals of 1 h during the last 3 h of each of the 6 h sampling periods, and at 6, 7 and 8 h after the beginning of sampling on day 10. There were significant (P < 0.001) group (zero-weaned versus suckled), time and morphine effects on LH secretion. Plasma LH concentrations increased (P < 0.001) within 48 h of farrowing in zero-weaned sows. Long-term trends of an increase in mean plasma LH in the sampling periods before treatment were attenuated in both groups by morphine treatment. Morphine also significantly inhibited (P < 0.05) prolactin secretion in suckled sows. In zero-weaned sows, plasma prolactin was already low at the start of sampling and did not change with time or in response to morphine treatment. Therefore, the inability to demonstrate an opioidergic involvement in the suckling-induced inhibition of LH secretion during the early post-partum period in sows is not due to a lack of opioid receptors. Furthermore, in suckled sows, morphine is stimulatory to systems that have an inhibitory effect on prolactin secretion. 相似文献
10.
D P Cardinali M I Vacas M I Keller Sarmiento G S Etchegoyen E N Pereyra H E Chuluyan 《Journal of steroid biochemistry》1987,27(1-3):565-571
The time course for the decrease in norepinephrine concentration of rat pineal explants in culture indicated a significant fall starting at the 4th hour and completed after 16-24 h of incubation. Significant decreases of serotonin and 5-hydroxyindoleacetic acid (HIAA) levels in tissue, an increase of HIAA/serotonin ratio, and an increase of melatonin production rate in vitro were also observed as a function of the incubation time. Estradiol (10(-7)-10(-5) M) increased rat pineal melatonin content, testosterone (10(-5) M) decreased it and progesterone was devoid of activity when incubated with explants for up to 6 h. The in vitro stimulatory effect of estradiol on rat pineal methoxyindole synthesis was blocked by propranolol but not by phentolamine; propranolol also blocked the increase of nuclear estradiol-receptor complex produced by estrogen exposure of pineal explants. TSH (1-100 ng/ml), growth hormone (10-100 ng/ml) and LH (10 ng/ml) augmented rat pineal melatonin content while 100 ng/ml of FSH decreased it significantly. Prolactin exerted a biphasic effect on rat pineal explants, the lowest concentration augmenting melatonin content while the high concentration depressed it. Deep, intermediate and superficial segments of guinea-pig pineal glands showed an increase in melatonin concentration after a 6-h incubation in the presence of 10(-7)-10(-5) M estradiol. 相似文献
11.
A. Faletti M. A. Chaud M. A. F. Gimeno A. L. Gimeno 《Prostaglandins, leukotrienes, and essential fatty acids》1988,34(3)
The effects of morphine on the constancy of spontaneous contractions (isometric developed TENSION = IDT and contractile FREQUENCY = CF), in uterine strips isolated from ovariectomized rats and the influence of naloxone, were explored. The inotropic responses to added prostaglandins (PGs) E2 and F2α and the influences of morphine and of morphine in the presence of naloxone on PG actions, were also determined. Moreover, the synthesis and outputs of PGs E and F from uteri and the effects of morphine alone and of morphine plus naloxone, were studied. Morphine (10−6 M) significantly depressed uterine constancy of IDT during the first hours following delivery, but its action on CF did not differ from controls. Naloxone, neither at 10−8 M nor at 10−6 M, altered the negative inotropoic influence of morphine on IDT. Exogenous PGs E2 and F2α, stimulated uterine inotropism in a concentration-dependent fashion. Morphine altered dose-response curves for exogenous PGE2, evoking a parallel surmountable shift to the right, but did not affect the inotropic action of added PGF2α. This antagonistic effect of the opioid was not altered by preincubation with naloxone. Basal synthesis and outputs of PGs E and F in uteri from ovariectomized rats were significantly depressed by morphine (10−6 M) but not altered by incubating tissues with morphine in presence of naloxone. Results are discussed in terms of a presumptive dual action of morphine on uterine motility, i.e., antagonizing PGE2 receptors and inhibiting the synthesis of some PGs by the uterus. These influences of morphine do not appear to be subserved by the activation of μ opioid receptors. Moreover, the possibility that endogenous opioids could play a relevant role modulating uterine PG influences, is also discussed. 相似文献
12.
Brain protein synthesis in a cell-free system was stimulated by 10(-8) M-ACTH1-24. This stimulatory effect was completely inhibited by aurintricarboxylic acid (ATA), an inhibitor of reinitiation of new peptide chains. The N-terminal peptide sequence 4-10 exerted a biphasic modulation of cell-free protein synthesis, i.e., a stimulation at low concentrations (10(-8) and 10(-10) M) and an inhibition at a high concentration (10(-4) M). The D-isomer, ACTH4-10-7-D-phe, also showed a biphasic modulation that, however, was in a direction opposite to that shown by ACTH4-10-7-L-phe at 10(-8) M and 10(-4) M. 相似文献
13.
The neuromodulatory action of adenosine and ATP was investigated in isolated guinea pig bronchial strip chain preparations contracted with electrical field stimulation. The tissues were placed in organ baths containing physiological salt solution and stimulated at 8-Hz frequency, 0.5-ms pulse duration, and 30 V (approximately 100 mA) for 5 s. Electrical field stimulation evoked a biphasic contraction of bronchial muscle, consisting of an initial contraction followed by a sustained contraction, which was mediated by intramural cholinergic and noncholinergic nerve stimulations, respectively. Adenosine, at concentrations greater than M, caused a concentration-dependent inhibition in the height of the noncholinergically mediated contraction, accompanied by a very weak inhibition on the cholinergically mediated response. ATP (10(-5) to 3 x 10(-3) M) also produced a similar inhibitory effect on the noncholinergically mediated contraction, but the inhibitory potency was less than that of adenosine. The inhibitory response to adenosine was enhanced by the pretreatment with dipyridamole (2 x 10(-6) M) but antagonized with aminophylline (10(-5) M). Contractions of bronchial muscle evoked by exogenous acetylcholine (2 x 10(-6) M) or substance P (2 x 10(-7) M) were significantly inhibited by the adenosine (3 x 10(-4) M) pretreatment. These data suggest that in isolated guinea pig bronchi adenosine selectively inhibits noncholinergic neurotransmission through prejunctional P1-purinoceptors. 相似文献
14.
Bell HJ Azubike E Haouzi P 《Journal of applied physiology (Bethesda, Md. : 1985)》2011,111(5):1296-1303
The purpose of this study was to examine the effects of a clinically relevant opioid on the production of augmented breaths (ABs) in unanesthetized animals breathing normal room air, using a dosage which does not depress breathing. To do this we monitored breathing noninvasively, in unrestrained animals before and after subcutaneous injection of either morphine, or a saline control. The effect of ketamine/xylazine was also studied to determine the potential effect of an alternative sedative agent. Last, the effect of naloxone was studied to determine the potential influence of endogenous opioids in regulating the normal incidence of ABs. Morphine (5 mg/kg) had no depressive effect on breathing, but completely eliminated ABs in all animals in room air (P = 0.027). However, when animals breathed hypoxic air (10% O(2)), animals did express ABs, although their incidence was still reduced by morphine (P < 0.001). This was not a result of sedation per se, as ABs continued at their normal rate in room air during sedation with ketamine. Naloxone had no effect on breathing or AB production, and so endogenous opioids are not likely involved in regulating their rate of production under normal conditions. Our results show that in unanesthetized animals breathing normal room air, a clinically relevant opioid eliminates ABs, even at a dose that does not cause respiratory depression. Despite this, hypoxia-induced stimulation of breathing can facilitate the production of ABs even with the systemic opioid present, indicating that peripheral chemoreceptor stimulation provides a potential means of overcoming the opioid-induced suppression of these respiratory events. 相似文献
15.
Effects of TRH or its analog DN-1417 (gamma-butyrolactone-gamma-carbonyl-L-histidyl-L- prolinamide ) and pentobarbital, alone or in combination, on oxygen consumption and cyclic AMP formation in rat cerebral cortex slices were investigated. The oxygen consumption of rat cerebral cortex slices as measured with a Warburg apparatus, increased linearly over time (0 to 60-min incubation at 37C). Addition of pentobarbital (1 to 7 x 10-4M) inhibited oxygen consumption, in a concentration-dependent manner, up to 45% of control. A concomitant application of DN-1417 (10-5M) or TRH (10-4M) and pentobarbital (5 x 10-4M) led to a partial recovery of the pentobarbital effect. The similar anti-pentobarbital effects were observed with the addition of carbachol (10-4M) or dibutyryl cyclic AMP (10-3M), but not norepinephrine (10-4M) or dopamine (10-4M). DN-1417, TRH, carbachol, norepinephrine or dopamine at 10-4M stimulated cyclic AMP formation in the cerebral cortex slices. Addition of pentobarbital (1 to 7 x 10-4M) inhibited the cyclic AMP formation, in a concentration-dependent manner. DN-1417, TRH or carbachol at 10-4M but not norepinephrine or dopamine at 10-4M significantly reversed the reduction of cyclic AMP formation induced by pentobarbital (5 x 10-4M). Atropine (10-4M) almost completely abolished DN-1417-, TRH- and carbachol-induced cyclic AMP formation in the presence and absence of pentobarbital. 相似文献
16.
Sokolowska-Mikolajczyk M Socha M Mikolajczyk T Chyb J Szymacha J Epler P 《Comparative biochemistry and physiology. Toxicology & pharmacology : CBP》2005,141(4):325-331
The in vitro effects of morphine (10(-10), 10(-8), 10(-6) or 10(-5) M) or/and naltrexone (10(-6) or 10(-8) M) on LH release from male and female carp (Cyprinus carpio L.) dispersed pituitary cells (obtained from fish at the time of late gonad recrudescence) were investigated. Morphine alone at the lowest tested concentration (10(-10) M) increased LH secretion from the cells of males. On the contrary, in female cell incubations the highest concentrations of morphine (10(-6) or 10(-5) M) significantly lowered LH levels. Naltrexone alone (at both tested concentrations) had no influence on LH secretion, neither in males nor in females. However in the incubations of female cells it antagonised the influence of morphine at 10(-10) or 10(-8) M. In male cell incubations naltrexone abolished the stimulatory action of morphine at 10(-10) M. The results suggest that in the in vitro culture of carp pituitary cells LH secretion is modulated by the opioids which affect the release of this gonadotropin through the typical opioid receptors and that the mu type of these receptors is involved in this process. The effects of opioid agonist and antagonist depend on the stage of gonadal maturity and the sex of fish i.e. the actual level of sex steroids. 相似文献
17.
18.
The generation of lipoxygenase products on the contraction elicited by prostaglandin (PG) F2 alpha was investigated in the guinea-pig isolated trachea. Indomethacin (5 x 10(-6) M) inhibited the response at low concentrations of PGF2 alpha while enhanced the response at higher concentrations of PGF2 alpha. Phenidone (10(-4) M) and nordihydroguaiaretic acid (NDGA, 3 x 10(-5) M) appeared to inhibit the PGF2 alpha response. The PGF2 alpha response augmented by indomethacin was dose-dependently inhibited by NDGA and a leukotriene (LT) antagonist, FPL55712. NDGA had no effect on the contraction elicited by histamine but markedly inhibited the contraction elicited by LTD4. The inhibition by NDGA of the LTD4-induced contraction was abolished in the presence of indomethacin (5 x 10(-6) M). FPL55712 inhibited the LTD4-induced contraction but the extent of the antagonism was not changed by indomethacin. In the presence of indomethacin PGF2 alpha (10(-8) M) did not affect the LTD4 (3 x 10(-9) M) response but significantly enhanced the arachidonic acid (AA, 6.6 x 10(-5) M)-induced contraction. FPL55712 (3 x 10(-6) M) completely inhibited the AA response augmented by PGF2 alpha. These results suggest that lipoxygenase-mediated LT-like substances are released in the response at higher concentrations of PGF2 alpha on the guinea-pig isolated trachea, and the mode of action of PGF2 alpha is different from those of histamine and LTD4. 相似文献
19.
Raman Preet Singh Sarbjit Singh Jhamb Prati Pal Singh 《Indian journal of microbiology》2009,49(3):276-282
The immunomodulatory effects of opioids are known in various infections. However, little is known about the effects of opioids
in tuberculosis (TB). In the present study, we report the effects of morphine in Mycobacterium smegmatis infection in mice and macrophages. Morphine exerted a dose-dependent suppression of infection in vivo: 50 and 100 mg/kg morphine
exerted significant (P<0.05) suppression whereas 5 mg/kg morphine showed no effect. Analogous to the in vivo effects, incubation
of M. smegmatis-infected mouse peritoneal macrophages with morphine (100 μM) showed significant reduction in intramacrophage CFU counts.
However, morphine did not show any direct antimycobacterial activity in broth dilution assay upto 100 μM concentration. Further,
morphine-induced intramacrophage killing of M. smegmatis was abrogated by naloxone and aminoguanidine indicating the involvement of opioid-receptor activation and nitric oxide production
in protective effects of morphine. In conclusion, morphine suppressed the progression of experimental TB in both mice and
macrophage models. 相似文献
20.
The effect of histamine (10(-9)-10(-3) M) on horse penile dorsal artery was evaluated. Precontracted vessels showed a biphasic response (relaxation-contraction) to histamine, while at basal tone, histamine only induced a contractile effect. The H1 receptor agonist, 2-pyridylethylamine (PEA) (10(-9)-10(-3) M), induced concentration-dependent relaxation in precontracted rings and provoked vasoconstriction at basal tone. Mepyramine (10(-9)-10(8) M), an H1 receptor antagonist, competitively antagonized the relaxant response to histamine (pA2 = 9.7) and PEA (pA2 = 9.2). At basal tone, mepyramine (10(-10)-10(-8) M) also caused a rightward shift in the histamine contraction curve (pA2 = 10.1). Mepyramine (10(-9)-10(-8) M)/PEA Schild plots for resting vessels yielded a pA2 value of 9.4. A regulatory role for H2 and H3 receptors was precluded since there was no response to their agonists (dimaprit (10(-9)-10(-3) M), (R)-alpha-methylhistamine (10(-10)- 3 x 10(-4) M)), and antagonists (cimetidine (10(-5) M), thioperamide (10(-6) M)) did not affect control curves. Removal of the endothelium abolished the relaxant component causing a leftward shift in the contractile component in precontracted rings, with no effect on maximum contraction. Inhibitors of nitric oxide (NO) synthesis, L-NAME (3 x 10(-4) M) and L-NOARG (3 x 10(-4) M), modified the relaxant response while contraction was unaffected. L-Arginine (3 x 10(-4) M) potentiated maximum relaxation but did not affect contraction in precontracted rings. Effects of a prostanoid and K+ channels were ruled out. The biphasic response of precontracted vessels persisted in the presence of indomethacin (3 x 10(-6) M), tetraethylammonium (10(-3) M) and gliblenclamide (10(-5) M). L-NAME plus indomethacin, or this combination plus TEA or glibenclamide produced similar effects as isolated treatments. In resting vessels, histamine contraction was also unaffected by the lack of endothelium, or L-NAME, L-arginine or indomethacin pretreatment. The biphasic response to histamine is probably mediated by H1 receptors with a partial role for NO in the relaxant response in precontracted vessels. In the absence of tone, the contractile effect may be mediated by direct action on smooth muscle. 相似文献